JP2007504265A - N- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1,3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide and LHRH analogs and Combinations containing / or bisphosphonates - Google Patents

Abstract

  N- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1,3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide, or a pharmaceutical thereof And salts containing LHRH analogs and / or bisphosphonates are described.

Description

Detailed Description of the Invention

  The present invention relates to N- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1,3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide or It relates to a combination comprising a pharmaceutically acceptable salt thereof (hereinafter “Compound (I)”) and a luteinizing hormone releasing hormone analog (hereinafter LHRH analog). Furthermore, the present invention relates to a combination comprising Compound (I) and a diphosphate derivative (hereinafter referred to as bisphosphonate), and a combination comprising Compound (I), an LHRH analogue and bisphosphonate.

  These combinations are useful for the treatment and prevention of cancer. The invention also relates to pharmaceutical compositions containing such combinations and their use in the manufacture of a medicament for use in the treatment and prevention of cancer, particularly prostate cancer.

  Cancer affects approximately 10 million people worldwide. This number includes occurrence, number of patients and number of deaths. Over 4.4 million cancer cases have been reported from Asia, including 2.5 million cases in East Asia, which is the highest incidence in the world. By comparison, Europe has 2.8 million cases, North America has 1.4 million cases, and Africa has 627,000 cases.

  In the UK and US, for example, more than one in three people will develop cancer at some point in their lives. U. S. The number of cancer deaths is estimated to be about 600,000 per year, about 1 per every 4 deaths, ranking second in all death rates after heart disease, and 1-14 Following the accident as the cause of death of an old child. U. S. The estimated number of cancers in is currently about 1,380,000 new cases per year, with the exception of about 900,000 cases of non-melanoma (basal and squamous cell) skin cancer.

  Cancer is also a major cause of morbidity in the UK, with approximately 260,000 new cases (excluding non-melanoma skin cancer) recorded in 1997. Cancer is a disease that primarily affects the elderly, with 65% of cases occurring in the elderly over the age of 65. Since the mid-19th century, life expectancy in the UK has almost doubled, increasing the population at risk for cancer. While death rates from other causes of death, such as heart disease, have declined in recent years, cancer deaths remain relatively unchanged. As a result, 1 in 3 people will be diagnosed with cancer in their lifetime and 1 in 4 people will die from cancer. In humans under 75 years of age, cancer deaths overwhelm cardiovascular deaths in numbers, including ischemic heart disease and stroke. In 2000, 151,200 people died from cancer. More than 1/5 (22 percent) of these are from lung cancer and 1/4 (26 percent) are from colon, breast and prostate cancer.

  Worldwide, the incidence and mortality of certain types of cancer (stomach, breast, prostate, skin, etc.) have significant geographical differences, which can be attributed to racial, cultural, and especially environmental impacts. to cause. Although there are more than 200 different cancer types, the four major types, lung, breast, prostate, and colon cancer, account for more than half of all cases diagnosed in the UK and US. Prostate cancer is the fourth most common male malignancy in the world, with an estimated 400,000 new cases diagnosed each year, accounting for 3.9 percent of all new cancer cases.

  Commonly used options for cancer treatment include surgical resection, external beam radiation therapy and / or systemic chemotherapy. These are partially successful in certain forms of cancer, but not in others. There is a clear need for new therapeutic treatments.

Recently, endothelin A receptor antagonists have potential to have utility in the treatment of cancer has been confirmed (Cancer Research, 56,663-668, February 15 th, 1996 and Nature Medicine, Volume1, Number9, September 1999 , 944-949).

Endothelin is an endogenous 21 amino acid peptide family that includes three isoforms, endothelin-1, endothelin-2 and endothelin-3. By endothelin-converting enzyme, endothelin by ^Trp 21 -Val ²² bond cleavage of the corresponding pro-endothelin is formed. Endothelin is one of the most potent vasoconstrictors known. They exhibit a variety of other activities, including the promotion of cell proliferation and mitogenesis, apoptosis, blood leaching and inhibition of chemotaxis, and also interact with a number of other vasoactive substances.

  Endothelin is released from a range of tissue and cell sources, including vascular endothelium, vascular smooth muscle, kidney, liver, uterus, airways, intestines and leukocytes. Release can be stimulated by hypoxia, shear stress, body injury and a wide range of hormones and cytokines. Elevated endothelin levels have been found in a number of disease states in humans, including cancer.

  LHRH is secreted from the hypothalamus into the pituitary portal circulation in response to nerve and / or chemical stimulation and causes decapeptides that cause luteinizing hormone (LH) and ovarian-stimulating hormone (FSH) biosynthesis and release by the pituitary gland It is. LHRH is also known as another name, gonadotropin releasing hormone (GnRH), gonadovelin, FSH releasing hormone (FSHRH) and LH / FSH releasing factor (LH / FSH RF).

  The role of gonad androgens in propagating and maintaining prostate cancer growth has long been recognized (Huggins C, Hodges CV. Cancer Res 1941; 1: 293). LHRH plays an important role in regulating the action of LH and FSH (by regulating their levels) and has a role in regulating gonadal steroid levels in both sexes, including the sex hormones progesterone, estrogens and androgens. Further description of LHRH can be found in WO 97/14697, the disclosure of which is hereby incorporated by reference.

  Medical and surgical castration are commonly used for the treatment of prostate cancer, and LHRH analogs are often used to induce medical castration for the treatment of patients with early and advanced prostate cancer. They have been shown to be effective in treating certain conditions that require inhibition of LH / FSH release. In particular, LHRH-based therapies include endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty and some gonadal steroid-dependent tumors, most notably prostate, breast and ovary Has been shown to be effective in the treatment of cancer. LHRH analogs are also utilized in various artificial insemination techniques and are being investigated as potential contraceptives in male and female therapy. They are also used in the treatment of growth hormone deficient children in the treatment of pituitary gonadotrophic adenoma, sleep disorders such as sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, hirsutism It has shown potential utility as an incidental to growth hormone therapy and in mouse models of lupus.

  Bisphosphonates are diphosphate derivatives that can regulate metal cation content (especially calcium content) in humans. In particular, they have a marked regulatory effect on calcium metabolism in warm-blooded animals. They are therefore useful in the treatment of diseases related to the content and circulation of these cations, especially the delay of bone demineralization. Most notably, they are Acta Endocinol. 78,613-24 (1975) significantly inhibits bone resorption in rats, as can be shown in the experimental procedure.

  The clinical use of bisphosphonates has increased dramatically over the past decade. The most common indication for these compounds is osteoporosis, and their use in osteolytic bone diseases is rapidly increasing. The FDA approved pamidronate in 1995 for the treatment of normal calcium blood patients with myeloma. In 1996, they issued a new approval for patients with metastatic breast cancer osteolytic lesions, encouraging widespread use of pamidronate in patients with tumors that metastasize to bone. The effect of bisphosphonates on osteoclast-mediated bone resorption is known and has been demonstrated for many years, but the exact mechanism of its inhibition remains unclear.

We unexpectedly:
i) combined use of compound (I) and LHRH analog; or ii) combined use of compound (I) and bisphosphonate; or iii) combined use of compound (I), LHRH analog and bisphosphonate;
Has been found to have specific advantages in the treatment of cancer.

Thus, according to the present invention, there is provided a combination comprising compound (I) and an LHRH analog.
According to an additional aspect of the present invention, there is provided a combination comprising compound (I) and a bisphosphonate.

In accordance with an additional aspect of the present invention, there are provided combinations comprising Compound (I), LHRH analogs and bisphosphonates.
As used herein, when the term “LHRH analog” is used, this is an agonist or antagonist at the LHRH receptor, whether by interaction with the LHRH binding site or by an allosteric mechanism. Represents any compound, or pharmaceutically acceptable salt thereof, including small molecules and peptides that act as, ie, act at a position on the LHRH receptor that is different from the LHRH binding site. In one aspect of the invention an “LHRH analog” refers to an LHRH antagonist, or a pharmaceutically acceptable salt thereof. In one aspect of the invention an “LHRH analog” refers to an LHRH agonist, or a pharmaceutically acceptable salt thereof. In an additional aspect of the invention, “LHRH analog” refers to a combination of an LHRH antagonist, or a pharmaceutically acceptable salt thereof and an LHRH agonist, or a pharmaceutically acceptable salt thereof.

  A “bisphosphonate” is a compound that can modulate the metal cation content (especially calcium content) in humans, or a pharmaceutically acceptable salt thereof, and is a compound containing two carbon phosphorus bonds. Additional description of the term “bisphosphonate” is found in Endocrine Reviews, 1998, 19 (1): 80-100, the contents of which are hereby incorporated by reference.

  As used herein, when the term “combination” is used, it should be understood to represent simultaneous, separate, or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention, “combination” refers to separate administration. In an additional aspect of the invention, “combination” refers to continuous administration. Where administration is continuous or separate, the delay in administration of the second component should not be such that it loses the synergistic benefit of the combination.

In one aspect, when referring to a compound or a pharmaceutically acceptable salt thereof, this represents only the compound. In another aspect this represents a pharmaceutically acceptable salt thereof.
When referring to cancer, among others it is esophageal cancer, myeloma, hepatocellular carcinoma, pancreatic cancer, cervical cancer, Ewing tumor, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colon cancer, prostate cancer, bladder cancer, Represents melanoma, lung cancer-non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, brain tumor, kidney cancer, lymphoma and leukemia. More specifically it represents prostate cancer. Furthermore, more specifically it represents SCLC, NSCLC, colon cancer, ovarian cancer and / or breast cancer. Furthermore, more specifically it represents SCLC. Furthermore, more specifically it represents NSCLC. Furthermore, more specifically it represents colon cancer. Furthermore, more specifically it represents ovarian cancer. Even more specifically it represents breast cancer. Furthermore, more specifically it represents bladder cancer, esophageal cancer, gastric cancer, melanoma, cervical cancer and / or kidney cancer. In addition, it represents endometrial cancer, liver cancer, gastric cancer, thyroid cancer, rectal cancer, and / or brain tumor. In another aspect of the invention, the cancer is not melanoma. In another aspect of the invention, among others, the cancer is in a metastatic state, and more specifically the cancer produces metastasis to bone. In additional embodiments of the invention, among others, the cancer is in a metastatic state, and more specifically the cancer produces skin metastasis. In additional embodiments of the invention, among others, the cancer is in a metastatic state, and more specifically, the cancer produces lymphatic metastasis. In an additional aspect of the invention, the cancer is in a non-metastatic state.

  When referring to the treatment of cancer, this is especially the treatment of cancerous tumors expressing endothelin A. This treatment relates to one or more of the extent of response, response speed, time to disease progression, and survival. The combined use of Compound (I) and specific LHRH analogs will have a beneficial effect in preventing the development of cancer in warm-blooded animals such as humans.

  Specific compounds having LHRH analog activity, or pharmaceutically acceptable salts thereof, include azaline B, A-198401, A-75998, A-76154, A-84861, abarelix, AN-152, AN-207, Antide, avorelin, cetrorelix, D-21775, D-23487, D-26344, D-63153, D-85108, degarelix, deslorelin ( deslorelin, detilelix, FE2000048, ganirelix, gonadimune, goserelin, hysterelin ( istrelin, leuprolide (leuprolide), leuprorelin (leuprorelin), metalrelin (metaarelin), nafarelin (nafarelin), NBI-42902 (Neurocrine), Org-30850, PH-45 (Pherin Corp. l, PT. ), RWJ-47428-021, SPD-424, sulfagon, T-66 (Matrix Therapeutics Ltd), TAK-013, TAK-810, teverelix, triptorelin acetate, triptorelin Moly (triptorelin pamoate) Include vomeropherins (vomeropherin) or ZK-157348.

A specific LHRH analog is a peptide or peptide derivative. Specific examples of LHRH agonists include, but are not limited to:
i) Buserelin (US Pat. No. 4,024,248)
^{(Pyr) Glu-His-Trp} -Ser-Tyr-D-Ser (Bu t) 6 -Leu-Arg-Pro-NHCH 2 CH 3
ii) Triptorelin (US Pat. No. 4,010,125)
(Pyr) Glu-His-Trp-Ser-Tyr-Trp-Leu-Arg-Pro-Gly-NH ₂
iii) Leuprorelin (US Pat. No. 4,050,063)
(Pyr) Glu-His-Trp -Ser-Tyr-D-Leu-Leu-Arg-Pro-NHCH 2 CH 3
iv) Goserelin (US Pat. No. 4,100,204)
^{(Pyr) Glu-His-Trp} -Ser-Tyr-D-Ser (Bu t) 6 -Leu-Arg-Pro- (Azygly) NH 2
v) Deslorelin (US Pat. No. 4,659,695)
(Pyr) Glu-His-Trp -Ser-Tyr-D-Trp-Leu-Arg-Pro-NH-CH 2 -CH 2 -NH 2
vi) Hysterelin (US Pat. No. 4,244,946)
(Pyr) Glu-His-Trp -Ser-Tyr-D-His (Bzl) -Leu-Arg-Pro-NH-CH 2 -CH 3
vii) Aborelin (US Pat. No. 5,668,254)
(Pyr) Glu-His-Trp -Ser-Tyr-D-Trp (2-Me) -Leu-Arg-Pro-NH-CH 2 -CH 3
viii) Nafarelin (US Pat. No. 4,234,571)
(Pyr) Glu-His-Trp -Ser-Tyr-D-Nal (2) -Leu-Arg-Pro-NH-CH 2 -CH 3;
Lutrelin, cystorelin, gonadorelin or detilelix.

In particular, the LHRH agonist is selected from leuprorelin, buserelin, triptorelin and goserelin. More particularly, the LHRH agonist is goserelin.
Examples of suitable LHRH antagonists include antid, abarelix, antarelix, cetrorelix, azaline, ganirelix and those described in the following US patents: No. 5470947 (Folkers); And 5300492 (Haviv); 5371070 (Koerber); 5296468 (Hoegar); 5171635 (Janaky); 5003011 and 4431635 (Coy); 4999421 (De); Nestor); and 4,851,385, 4,689396, and 5,843,901 (Roeske).

  Additional examples of suitable LHRH antagonists include, but are not limited to, the compounds described in WO02 / 066477, WO02 / 066478, WO02 / 066459, WO02 / 092565, PCT / GB03 / 003603 and PCT / GB03 / 003606. And these patent applications, in particular the compounds described in claim 1 and the examples given, are hereby incorporated by reference.

  Specific bisphosphonates for use in the present invention are tiludronic acid, ibandronic acid, incadronic acid, risedronic acid, zoledronic acid, clodronic acid, neridronic acid, pamidronic acid, alendronic acid, minodronic acid, olpadronic acid, TRK530, CGP47072, Selected from calcium clodronate or EB1053. Additional specific bisphosphonates for use in the present invention are selected from etidronic acid, PNU-91638, NE-21650, NE-58025, NE-10790 or NE-10446.

Specific combinations of the present invention include the following:
-Compound (I) and leuprorelin, or a pharmaceutically acceptable salt thereof;
-Compound (I) and goserelin, or a pharmaceutically acceptable salt thereof;
Compound (I) and abarelix, or a pharmaceutically acceptable salt thereof;
-Compound (I) and cetrorelix, or a pharmaceutically acceptable salt thereof;
-Compound (I) and risedronic acid, or a pharmaceutically acceptable salt thereof;
-Compound (I) and zoledronic acid, or a pharmaceutically acceptable salt thereof;
-Compound (I) and clodronic acid, or a pharmaceutically acceptable salt thereof;
Compound (I) and pamidronic acid, or a pharmaceutically acceptable salt thereof;
Compound (I) and alendronic acid, or a pharmaceutically acceptable salt thereof.

  Suitable pharmaceutically acceptable salts thereof include, for example, alkali metal (eg, sodium, potassium or lithium), salts with alkaline earth metals (eg, calcium or magnesium), ammonium salts, and physiologically acceptable cations. And salts with organic bases that yield, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine. In addition, for compounds that are sufficiently basic, suitable pharmaceutically acceptable salts include hydrogen halides, sulfuric acid, phosphoric acid and citric acid, maleic acid, methanesulfonic acid and p-toluenesulfonic acid. And pharmaceutically acceptable acid addition salts with other organic acids. Alternatively, the compound may exist in zwitterionic form.

Therefore, in accordance with the present invention, there is provided a combination comprising compound (I) and an LHRH analog for use as a medicament.
Therefore, according to the present invention there is provided a combination comprising compound (I) and a bisphosphonate for use as a medicament.

Therefore, in accordance with the present invention, there is provided a combination comprising Compound (I), LHRH analog and bisphosphonate for use as a medicament.
According to an additional aspect of the present invention, there is provided a pharmaceutical composition comprising Compound (I) and an LHRH analog, with a pharmaceutically acceptable diluent or carrier.

According to an additional aspect of the present invention there is provided a pharmaceutical composition comprising compound (I) and a bisphosphonate with a pharmaceutically acceptable diluent or carrier.
According to an additional aspect of the present invention, there is provided a pharmaceutical composition comprising compound (I), an LHRH analog and a bisphosphonate, with a pharmaceutically acceptable diluent or carrier.

  In accordance with an additional aspect of the invention, compound (I) with a pharmaceutically acceptable diluent or carrier in combination with a pharmaceutical composition containing an LHRH analog with a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition is provided.

  In accordance with an additional aspect of the present invention, containing Compound (I) with a pharmaceutically acceptable diluent or carrier in combination with a pharmaceutical composition containing a bisphosphonate with a pharmaceutically acceptable diluent or carrier A pharmaceutical composition is provided.

  According to an additional aspect of the present invention, a pharmaceutical composition in combination with a pharmaceutical composition comprising an LHRH analog with a pharmaceutically acceptable diluent or carrier and a bisphosphonate with a pharmaceutically acceptable diluent or carrier There is provided a pharmaceutical composition containing compound (I) with an acceptable diluent or carrier.

  Therefore, in accordance with the present invention, treating cancer in an animal in need of such treatment comprising administering to a warm-blooded animal such as a human an effective amount of Compound (I) in combination with an effective amount of an LHRH analog. A method is provided.

  Therefore, there is provided a method of treating cancer in an animal in need of such treatment comprising administering to a warm-blooded animal such as a human an effective amount of Compound (I) in combination with an effective amount of a bisphosphonate according to the present invention. Provided.

  Therefore, an animal in need of cancer treatment comprising administering to a warm-blooded animal such as a human an effective amount of Compound (I) in combination with an effective amount of an LHRH analog and an effective amount of a bisphosphonate according to the present invention. A method of treating cancer in is provided.

  For the avoidance of doubt, when referring to cancer treatment, this should also be understood to represent metastasis, the prevention and treatment of cancer spread. Therefore, the combination of the present invention treats the metastasis itself of patients who have already metastasized, to prevent patients without metastasis from developing them, or to extend the period until they occur. Can be used to Furthermore, the treatment of cancer also refers to the treatment of an established primary tumor or tumors and a developing primary tumor or tumors. In one aspect of the invention, treating cancer represents prevention of metastasis. In another aspect of the invention, treating cancer represents treating metastasis. In another aspect of the invention, the treatment of cancer represents the treatment of an established primary tumor or tumors and a developing primary tumor or tumors. As used herein, treatment of cancer further refers to prevention of the cancer itself.

Furthermore, the treatment of cancer also represents the generation of an anti-angiogenic effect in warm-blooded animals.
In accordance with an additional aspect of the invention, a kit is provided comprising compound (I) and an LHRH analog, optionally with instructions.

In accordance with an additional aspect of the invention, a kit is provided comprising compound (I) and a bisphosphonate, optionally with instructions.
In accordance with an additional aspect of the invention, a kit is provided comprising compound (I), an LHRH analog and a bisphosphonate, optionally with instructions.

In accordance with additional aspects of the present invention, kits are provided that include:
a) Compound (I) in the first unit dosage form;
b) LHRH analogs in a second unit dosage form; and c) container means for containing the first and second dosage forms described above; and optionally d) instructions for use.

  An example of a unit dosage form of Compound (I) may be a tablet for oral formulation, see those described herein below. Examples of unit dosage forms of LHRH analogs include sustained release formulations for LHRH agonists (see below), or sustained release or tablet formulations for LHRH antagonists (see below). (See).

In accordance with additional aspects of the present invention, kits are provided that include:
a) Compound (I) in the first unit dosage form;
b) a bisphosphonate in a second unit dosage form; and c) a container means for containing the first and second dosage forms described above; and optionally d) instructions for use.

Examples of unit dosage forms of bisphosphonates include tablet formulations for oral formulations, see below in this specification.
In accordance with additional aspects of the present invention, kits are provided that include:
a) Compound (I) in the first unit dosage form;
b) an LHRH analogue in the second unit dosage form; and c) a bisphosphonate in the third unit dosage form; and d) a container means for containing the first, second and third dosage forms as described above; and E) Instruction manual.

In accordance with additional aspects of the present invention, kits are provided that include:
a) Compound (I) in a first unit dosage form together with a pharmaceutically acceptable diluent or carrier;
b) LHRH analogs in a second unit dosage form; and c) container means for containing the first and second dosage forms described above; and optionally d) instructions for use.

In accordance with additional aspects of the present invention, kits are provided that include:
a) Compound (I) in a first unit dosage form together with a pharmaceutically acceptable diluent or carrier;
b) a bisphosphonate in a second unit dosage form; and c) a container means for containing the first and second dosage forms described above; and optionally d) instructions for use.

In accordance with additional aspects of the present invention, kits are provided that include:
a) Compound (I) in a first unit dosage form together with a pharmaceutically acceptable diluent or carrier;
b) an LHRH analog in the second unit dosage form; and c) a bisphosphonate in the third unit dosage form; and d) a container means for containing the first, second and third dosage forms as described above; and optionally e) Instruction manual.

  According to an additional aspect of the present invention, there is provided a pharmaceutical composition comprising Compound (I) and an LHRH analog with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.

  According to an additional aspect of the present invention there is provided a pharmaceutical composition comprising Compound (I) and a bisphosphonate with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.

  In accordance with an additional aspect of the present invention, Compound (I), an LHRH analog with a pharmaceutically acceptable diluent or carrier, and a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer A pharmaceutical composition containing a bisphosphonate is provided.

  In accordance with an additional aspect of the present invention, a pharmaceutically acceptable diluent in combination with a pharmaceutical composition containing a pharmaceutically acceptable diluent or LHRH analog with a carrier for use in the treatment of cancer. Or the pharmaceutical composition containing the compound (I) with a carrier is provided.

  According to an additional aspect of the present invention, a pharmaceutically acceptable diluent or carrier in combination with a pharmaceutical composition containing a bisphosphonate with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer. There is provided a pharmaceutical composition comprising compound (I) with

  In accordance with an additional aspect of the invention, containing an LHRH analog with a pharmaceutically acceptable diluent or carrier and a bisphosphonate with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer A pharmaceutical composition containing compound (I) with a pharmaceutically acceptable diluent or carrier in combination with a pharmaceutical composition is provided.

  The pharmaceutical composition is in a form suitable for oral administration (eg, as a tablet or capsule), in a form suitable for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) (eg, sterile solution, suspension) As an agent or emulsion), in a form suitable for topical administration (eg, as an ointment or cream), or in a form suitable for rectal administration (eg, as a suppository). In general, the compositions described above can be prepared in a conventional manner using conventional additives.

For example, Compound (I) can be formulated as a tablet using the following additives:
Compound (I);
Lactose monohydrate (bulking agent);
Croscarmellose sodium (disintegrant);
Povidone (binder);
Magnesium stearate (lubricant);
Hypromellose (film coating component);
Polyethylene glycol 300 (film coating component); and titanium dioxide (film coating component).

In accordance with an additional aspect of the present invention, there is provided a kit comprising Compound (I) and an LHRH analog, optionally with instructions, for use in the treatment of cancer.
In accordance with an additional aspect of the invention, a kit is provided comprising Compound (I) and a bisphosphonate, optionally with instructions, for use in the treatment of cancer.

  In accordance with an additional aspect of the present invention, there is provided a kit comprising Compound (I), LHRH analogs and bisphosphonates, optionally with instructions, for use in the treatment of cancer.

In accordance with an additional aspect of the invention, a kit is provided for use in the treatment of cancer comprising:
a) Compound (I) in the first unit dosage form;
b) LHRH analogs in a second unit dosage form; and c) container means for containing the first and second dosage forms described above; and optionally d) instructions for use.

In accordance with an additional aspect of the invention, a kit is provided for use in the treatment of cancer comprising:
a) Compound (I) in the first unit dosage form;
b) a bisphosphonate in a second unit dosage form; and c) a container means for containing the first and second dosage forms described above; and optionally d) instructions for use.

In accordance with an additional aspect of the invention, a kit is provided for use in the treatment of cancer comprising:
a) Compound (I) in the first unit dosage form;
b) an LHRH analog in the second unit dosage form; and c) a bisphosphonate in the third unit dosage form; and d) a container means for containing the first, second and third dosage forms as described above; and optionally e) Instruction manual.

In accordance with an additional aspect of the invention, a kit is provided for use in the treatment of cancer comprising:
a) Compound (I) in a first unit dosage form together with a pharmaceutically acceptable diluent or carrier;
b) LHRH analogs in a second unit dosage form; and c) container means for containing the first and second dosage forms described above; and optionally d) instructions for use.

In accordance with an additional aspect of the invention, a kit is provided for use in the treatment of cancer comprising:
a) Compound (I) in a first unit dosage form together with a pharmaceutically acceptable diluent or carrier;
b) a bisphosphonate in a second unit dosage form; and c) a container means for containing the first and second dosage forms described above; and optionally d) instructions for use.

In accordance with an additional aspect of the invention, a kit is provided for use in the treatment of cancer comprising:
a) Compound (I) together with a pharmaceutically acceptable diluent or carrier in a first unit dosage form;
b) an LHRH analog in the second unit dosage form; and c) a bisphosphonate in the third unit dosage form; and d) a container means for containing the first, second and third dosage forms as described above; and optionally e) Instruction manual.

According to another aspect of the present invention there is provided the use of compound (I) in combination with an LHRH analogue in the manufacture of a medicament for use in the treatment of cancer in warm-blooded animals such as humans.
According to another aspect of the present invention there is provided the use of compound (I) in combination with a bisphosphonate in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal such as a human.

  According to another aspect of the present invention there is provided the use of compound (I) in combination with an LHRH analog and a bisphosphonate in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal such as a human.

According to another aspect of the present invention there is provided the use of compound (I) in combination with LHRH analogues in the treatment of cancer in warm-blooded animals such as humans.
According to another aspect of the present invention there is provided the use of compound (I) in combination with a bisphosphonate in the treatment of cancer in warm-blooded animals such as humans.

According to another aspect of the present invention there is provided the use of Compound (I) in combination with LHRH analogs and bisphosphonates in the treatment of cancer in warm-blooded animals such as humans.
In accordance with an additional aspect of the invention, there are provided combinations comprising Compound (I) and LHRH analogs for use in the treatment of cancer.

According to an additional aspect of the present invention, there is provided a combination comprising Compound (I) and a bisphosphonate for use in the treatment of cancer.
In accordance with an additional aspect of the invention, there are provided combinations comprising Compound (I), LHRH analogs and bisphosphonates for use in the treatment of cancer.

  In accordance with additional aspects of the present invention, optionally pharmaceutically acceptable dilution, in combination with an effective amount of LHRH analog, optionally together with a pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer. Combination therapies are provided, including administration of an effective amount of Compound (I) together with an agent or carrier to a warm-blooded animal such as a human in need of such therapeutic treatment.

  According to an additional aspect of the present invention, an optional pharmaceutically acceptable diluent or combination with an effective amount of bisphosphonate, optionally together with a pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer Combination therapies are provided, including administration of an effective amount of Compound (I) with a carrier to a warm-blooded animal such as a human in need of such therapeutic treatment.

  In accordance with an additional aspect of the invention, an effective amount of an LHRH analog, optionally with a pharmaceutically acceptable diluent or carrier, and optionally a pharmaceutically acceptable diluent or for use in the treatment of cancer Warm blood like a human in need of such therapeutic treatment of an effective amount of Compound (I), optionally in combination with an effective amount of a bisphosphonate with a carrier, optionally with a pharmaceutically acceptable diluent or carrier. Combination therapies are provided, including administration to animals.

  The amount of Compound (I), or a pharmaceutically acceptable salt thereof, administered will be sufficient to provide the desired pharmaceutical effect. For example, Compound (I) can be administered orally to warm-blooded animals at a unit dose of less than 1 g per day but greater than 2.5 mg. In particular, compound (I) can be administered to warm-blooded animals in a single dose of less than 250 mg per day. In another aspect of the invention, Compound (I) can be administered to warm-blooded animals in a single dose of less than 130 mg per day. In an additional aspect of the invention, Compound (I) can be administered to warm-blooded animals in a single dose of less than 50 mg per day.

  LHRH analogs, particularly LHRH agonists, will usually be administered as a sustained release formulation to enhance the therapeutic efficacy of the drug. A number of sustained release formulations containing LHRH analogs are known and can be achieved by administering the drug in the form of a biodegradable polymer matrix that releases the drug over an extended period of time. A suitable biodegradable polymer is polylactide. The term 'polylactide' has the general meaning to include polymers only of lactic acid, copolymers of lactic acid and glycolic acid, mixtures of such polymers, mixtures of such copolymers and mixtures of such polymers and copolymers. And lactic acid is either racemic or optically active.

  One approach has been to develop microparticle or microcapsule formulations containing biodegradable polymers, typically poly (lactide-co-glycolide) copolymers, in which LHRH analogs are micro Encapsulated.

EP 839525 describes the production of microcapsules containing LHRH analogues using an emulsion based process, in which an internal aqueous phase containing LHRH analogues and a solution of lactic acid polymer in an organic solvent are prepared. A water-in-oil emulsion containing the containing external oil phase is produced. In general, microencapsulated LHRH analogs are suitable for delivering LHRH analogs for up to 3 months EP 058881 is a monolithic implant containing biodegradable poly (lactide-co-glycolide) copolymers and LHRH agonists Describe.

  WO 03/022297 describes a monolithic implant manufactured using a combination of a specific polylactide polymer and an LHRH analog, which is continuously LHRH-like for at least 6 months when placed in an aqueous physiological-type environment. Release the body.

WO 03/022243 describes sustained release microcrystalline peptide suspensions containing LHRH agonists.
As an alternative, Eligard (LHRH agonist) is marketed as a flowable polymer formulation consisting of poly (DL-lactide) suspended in the non-aqueous solvent N-methyl-2-pyrrolidone.

  In addition to being delivered in the same manner by any of the sustained release methods listed above, LHRH antagonists can be formulated for oral administration using standard techniques and known additives.

  LHRH analogs will normally be administered to a warm-blooded animal in a unit dose, for example, about 3-4 mg per month, or 10-11 mg every 3 months. When the LHRH analog is goserelin, the sustained release subcutaneous formulation contains 3.6 mg active ingredient per month, or 10.6 mg every 3 months. Conveniently, the daily oral dose of leuprorelin is 3.75 mg per month, or 11.25 mg every 3 months. However, the optimal dosage may be determined by the physician treating the particular patient.

  Bisphosphonates will normally be administered to warm-blooded animals in unit doses, amounts known to those skilled in the art as therapeutically effective amounts. In the case of a single dosage form, the active ingredient may be formulated with an appropriate and convenient amount of additive, and the amount of additive may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 20 mg to about 500 mg of each active ingredient. However, the daily dose will necessarily be varied depending upon the recipient treated, the particular route of administration, and the severity of the illness being treated. Thus, the optimal dose may be determined by a physician treating a particular patient.

  The dosage of each drug and their proportions fits the most likely therapeutic effect as defined in national and international guidelines (which are reviewed and redefined regularly) Must be configured to do.

Claims (14)

  N- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1,3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide or pharmaceutically A combination comprising an acceptable salt and an LHRH analog.   N- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1,3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide or pharmaceutically A combination comprising an acceptable salt and a bisphosphonate.   N- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1,3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide or pharmaceutically A combination comprising an acceptable salt, an LHRH analog, and a bisphosphonate.   4. A combination according to claim 1 or 3 wherein the LHRH analogue is an LHRH agonist.   5. A combination according to claim 4 wherein the LHRH agonist is selected from leuprorelin, buserelin, triptorelin and goserelin.   6. A combination according to claim 4 or 5, wherein the LHRH agonist is goserelin.   4. A combination according to claim 1 or 3 wherein the LHRH analogue is an LHRH antagonist.   8. A combination according to claim 7, wherein the LHRH antagonist is selected from antide, abarelix, antarelix, cetrorelix, azaline or ganirelix.   The bisphosphonate is selected from tiludronic acid, ibandronic acid, incadronic acid, risedronic acid, zoledronic acid, clodronic acid, neridronic acid, pamidronic acid, alendronic acid, minodronic acid, olpadronic acid, TRK530, CGP47072, calcium clodronate or EB1053 The combination according to any one of claims 2 to 8.   A combination according to any one of claims 1 to 9 for use as a medicament.   10. A pharmaceutical composition according to any one of claims 1 to 9 with a pharmaceutically acceptable diluent or carrier.   10. A method of treating cancer in an animal comprising administering an effective amount of a combination according to any one of claims 1-9 to a warm-blooded animal, such as a human, in need of cancer treatment.   10. A pharmaceutical composition comprising a combination according to any one of claims 1 to 9 with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.   Use of a combination according to any one of claims 1 to 9 in the manufacture of a medicament for use in the treatment of cancer in warm-blooded animals such as humans.